The goal of this proposal seeks to develop a continuum-based mathematical model to gain a fundamental knowledge necessary to design a label-free, low-cost, high-speed, and high-throughput DNA sequencing method using nanopores. Nanopores are emerging as a promising candidate for the development of a third- generation sequencing device which will meet the goal of a $1,000 human genome sequencing paradigm set by the National Institute of Health. Many experimental data on DNA molecule translocation through a nanopore has been collected for the last decade, but a simple continuum-based model that describes the translocation process in statistical terms and can be directly compared with an ensemble average observed by experiments is still lacking. Limited existing analytical continuum models still cannot fully explain experimental observations. Simple physical arguments suggest that concentration polarization and the shape of the nanopore may be able to bridge the discrepancy of the tether force or translocation velocity between the experimental results and the theoretical predictions from existing simple continuum models. Thus the specific aims are to (1) Explore the role of concentration polarization using our proposed continuum-based mathematical model; (2) Examine the feasibility of using salt concentration imposed externally across the nanopore to regulate DNA translocation through numerical simulations; (3) Understand the effect of irregular shape of nanopores on DNA translocation. More accurate explicit relations between the translocation velocity and various conditions (e.g., salt concentration, nanopore dimension, surface charge, and the electric field intensity) will be determined by the proposed continuum model and ready to be directly compared with large amount of existing experimental data. Such information is important to understand the DNA translocation through a nanopore and further provides a knowledge base for rational design of experiments. PUBLIC HEALTH RELEVANCE: The outcome of this research may pave the road towards developing a third-generation DNA sequencing technology with the combination of high throughput, low cost, and high accuracy. This would revolutionize genomic medicine and change the future of medical fields through personal genomics.